Cutaneous leishmaniasis can be either a spontaneously healing or chronic disease, depending upon the strain of the parasite and the immunological status of the host. Using murine models, we are investigating both parasite and host factors responsible for the variable pathogenesis observed in leishmanial infections. C57BL/6 or C3H mice heal infections with L. tropica, but fail to heal following infection with the Maria strain, a L. mexicana strain isolated from a mucocutaneous leishmaniasis patient. In vitro studies have shown that the Maria strain is resistant to activated macrophage killing, while L. tropica is susceptible. This resistance to killing was observed in macrophages activated by lymphokines obtained from either BCG, L. tropica-, or Maria strain infected mice, and was shown not to be due to parasite-induced inhibition of killing mechanisms, since Maria strain-infected, lymphokine-activated, macrophages exhibited tumoricidal and toxoplasmacidal activity similar to uninfected macrophages. However, we have found that during phagocytosis of Maria, macrophages show a significantly smaller respiratory burst than when engesting L. tropica. We are currently pursuing the possibility that this difference in the production of oxygen intermediates may be a major factor in the resistance of Maria to killing. We are also examining host immunological factors which influence leishmaniasis using BALB/c mice. Although these mice are extremely susceptible to leishmanial infection, they show almost complete resistance following vaccination. We are comparing normal and vaccinated animals to determine what immune mechanisms are responsible for th protection seen in these mice. Although these mice do not show delayed hypersensitivity responses, peritoneal macrophages exhibited leishmanistatic activity when tested in an in vitro system. In addition, macrophages from infected mice lost the ability to respond to lymphokine, while macrophages from infected vaccinated mice did not. T lymphocytes from vaccinated mice respond to leishmanial antigens and continuous T cell lines have been established.